HIV 1 is maintained in a latent proviral state in T-cells, but can be induced by a number of external stimuli but the mechanisms by which this induction occurs are poorly understood. Most likely they involve activation of signal transduction pathways that induce transcription from the promoters on the HIV-LTR resulting in activation of the latent provirus. Signal transduction in eukaryotic cells involves protein-protein interactions, to propagate the biochemical cascade from one protein to another. The discovery of SH2 and SH3 domains on some signaling proteins has shed considerable light on two types of protein-protein interactions involved in cell signaling reactions, including reactions that induce the HIV-LTR provirus. Pleckstrin Homology (PH) domains have also been found on many proteins (now more than 120) in eukaryotes and are thought to require protein-protein interaction to mediate signal transduction. Recently we characterized a Dictyostelium gene, DdK6, which encodes a protein kinase containing a PH domain, and is essential for normal development and signal transduction. DdK6 is a homolog of the human rac protein kinase, which is expressed in T-cells. Rac is the proto- oncogene for the related retroviral oncogene v-akt, which causes T-cell lymphomas in rodents. This protein kinase family is now called protein kinase B and its functions in signal transduction pathways has been the topic of intense study. Proteins involved in their signaling pathways appear to be highly conserved between divergent species. We propose to test the hypothesis that PH domains are involved in important signal transduction pathways that activate genes including the HIV proviral genes.;